Brachytherapy with Intratumoral Injections of Radiometal-Labeled Polymers That Thermoresponsively Self-Aggregate in Tumor Tissues

Abstract

Brachytherapy is a type of radiotherapy wherein titanium capsules containing therapeutic radioisotopes are implanted within tumor tissues, enabling high-dose radioirradiation to tumor tissues around the seeds. Although marked therapeutic effects have been demonstrated, brachytherapy needs a complicated implantation technique under general anesthesia and the seeds could migrate to other organs. The aim of this study was to establish a novel brachytherapy using biocompatible, injectable thermoresponsive polymers (polyoxazoline [POZ]) labeled with Y, which can self-aggregate above a specific transition temperature (Tt), resulting in long-term intratumoral retention of radioactivity and therapeutic effect. Therefore, we evaluated the tumor retention of radiolabeled POZ derivatives and their therapeutic effects. Using oxazoline derivatives with ethyl (Et), isopropyl (Isp), and propyl (Pr) side chains, we synthesized EtPOZ, IspPOZ, Isp-PrPOZ (heteropolymer), and PrPOZ and measured their characteristic Tts. The intratumoral retention of In-labeled POZ was evaluated until 7 d after injection in nude mice bearing PC-3 human prostate cancer. The intratumoral localization ofIn-labeled POZ derivatives was investigated by an autoradiographic study. Furthermore, a therapeutic study using Y-labeled Isp-PrPOZ was performed, and tumor growth and survival rate were evaluated. The Tts of EtPOZ, IspPOZ, Isp-PrPOZ, and PrPOZ (∼20 kDa) were greater than 70°C, 34°C, 25°C, and 19°C, respectively. In the intratumoral injection study, Isp-PrPOZ and PrPOZ (2,000 μM) with Tts lower than tumor temperature (33.5°C under anesthesia) showed a significantly higher retention of radioactivity at 1 d after injection (73.6% and 73.9%, respectively) than EtPOZ (5.6%) and IspPOZ (15.8%). Even at low injected dose (100 μM), Isp-PrPOZ exhibited high retention (68.3% at 1 d). The high level of radioactivity of Isp-PrPOZ was retained in the tumor 7 d after injection (69.5%). The autoradiographic study demonstrated that the radioactivity of In-labeled Isp-PrPOZ and PrPOZ was localized in a small area. In the therapeutic study usingY-labeled Isp-PrPOZ, significant suppression of tumor growth and prolonged survival rate were achieved in an injection dose-dependent manner compared with that observed for the vehicle-injected group and nonradioactive Isp-PrPOZ-injected group. The injectableY-labeled Isp-PrPOZ was retained for a prolonged period within tumor tissues via self-aggregation and exhibited marked therapeutic effect, suggesting its usefulness for brachytherapy.

Enhanced Delivery of Thermoresponsive Polymer-Based Medicine into Tumors by Using Heat Produced from Gold Nanorods Irradiated with Near-Infrared Light

“…Furthermore, a Lu-177-labeled peptide-based radiopharmaceutical (Lu-177-dotatate) targeting somatostatin receptor 2, which is highly expressed in neuroendocrine tumors, was approved by the Food and Drug Administration [ 31 ]. POZ–DOTA could also be labeled with these therapeutic radiometals as previously reported [ 23 ]; therefore, the application of this strategy using a radiolabeled thermoresponsive POZ would be expected for efficient internal radiotherapy of tumors.…”

“…A POZ derivative was synthesized as described in our previous report [ 23 ]. Its molecular structure in this study is shown in Figure 2 .…”

[11C]Carboxylated Tetrazines for Facile Labeling of Trans‐Cyclooctene‐Functionalized PeptoBrushes

“…[ 2–4 ] Polymers and polymeric gels can be used as injectable biodegradable depots for controlled release of therapeutic payload or long‐term retention of drugs or therapeutic radiation sources (brachytherapy). [ 5–8 ]…”

“…[2][3][4] Polymers and polymeric gels can be used as injectable biodegradable depots for controlled release of therapeutic payload or long-term retention of drugs or therapeutic radiation sources (brachytherapy). [5][6][7][8] Theranostic applications of engineered macromolecules can be greatly enhanced by bio-orthogonal click chemistry, since it enables side specific labeling or drug release inside the body. Modification with click-reactive chemical tags gives macromolecules the capability to capture, retain or release small-molecular payload, which can be a radioactive or fluorescent label for diagnostic imaging, a therapeutic radionuclide or a drug.…”

<i>In Vivo</i> Molecular Imaging

“…Therefore this therapeutic strategy using 90 Y-labeled POZ derivatives may be promising for brachytherapy, a typical radiotherapy using "seeds" containing therapeutic radioisotopes. 89) We also developed an injectable 15 O oxygen obtained after 15 O-O 2 gas circulation into artificial lung and estimated changes in oxygen metabolism after occluding the middle cerebral artery in hypertensive rats using it. Consequently, we found that hypertension intensifies metabolic disturbances after the onset of strokes.…”